WHITE PAPER: Alternative Sources of Pluripotent Stem CellS

Table of Contents

The President's Council on Bioethics
Washington, D.C.
May 2005
www.bioethics.gov

Personal Statements

The preceding text constitutes the official body of this White Paper; it stands as the work of the entire Council. In the interest of contributing further to public discussion of the issues, and of enabling individual members of the Council to speak in their own voice on one or another aspect of this White Paper, we offer in this Appendix personal statements from those members who have elected to submit them:

Statement of Michael S. Gazzaniga, Ph.D.     

Statement of Robert P. George, D.Phil., J.D.,(joined by Mary Ann Glendon, J.D., M. Comp. L., and Alfonso Gómez-Lobo, Dr. phil.)

Statement of William B. Hurlbut, M.D.          

Statement of Janet D. Rowley, M.D., D.Sc.      

***

Personal Statement of Dr. Gazzaniga

I do not support publishing this report with the implied endorsement that special efforts be made in the scientific areas described. While some of the suggestions could be explored in a scientific setting, most are high-risk options that only have an outside chance of success and raise their own complex set of ethical questions. Of primary concern: this effort is a diversion from the simple task at hand which is to move forward with the established laboratory techniques, that are already grounded on a clear ethical basis, for studying embryonic stem cell research and biomedical cloning.

The simple proposals that are now widely accepted by the majority of ethicists and scientists alike are as follows:

Allow the use of spare IVF embryos to develop more human stem cell lines. These are entities that do not possess a single neuron and are ready to go and can create tens of thousands of cell lines. Put another way, a piece of DNA is not a human being. A human being is an entity with a functioning brain consisting of billions of neurons with trillions of synapses that develops over time and with crucial interactions with the environment.

Allow biomedical cloning (SCNT) to go forward.This laboratory procedure has been tested and it works. SCNT can only be carried out in a laboratory and the 14-day-old entity that results from the procedure also has not a single neuron. After the specific stem cells are harvested by 14 days, the remaining tissue is disposed of.

From a purely scientific point of view I offer the following remarks on the alternative suggestions made by the Council, based on consultation with stem cell experts:

Proposal 1, the Landry-Zucker proposal, is absolutely dependent on defining a battery of "death markers." The criteria they offer lack the specificity and selectivity required. To what degree, for example is "embryo-dead" analogous to "brain dead?" What are the long-term consequences (through adulthood) of using blastomeres from "dead" morulae? These are answerable, but formidable problems. Blastomere removal must be validated in vitro and in vivo, with respect to mitosis, survival, differentiation, etc., none of which are inaccessible. No assumption whatsoever can be made that these are "normal cells." At the same time, these questions are scientifically accessible.

Proposal 2, relies on biopsy, and this represents a new field, which must be explored experimentally. For example, and most obviously, what is the relationship of cellular to organ removal and transplantation? Are the biological rules homologous? We need the data.

Proposal 3, Bill Hurlbut's proposal, is also scientifically tractable, though fraught with ethical conundrums. Defective nuclear transfer could certainly be accomplished in theory, though issues of viability, etc., would be paramount. And replacing genes at the "wrong" time could be devastating either acutely or chronically. Although a myriad of additional potential problems could be cited, they are again empirical, not theoretical. Why delay what we know works with this sideshow? As pointed out in the paper, one of the leading stem cell research scientists in the world, Dr. Doug Melton at Harvard, has written an article in the New England Journal of Medicine dismissing this idea both scientifically and practically.

Proposal 4, dedifferentiation, is similarly approachable scientifically, though it is a high-risk strategy. Questions, however, raised with this idea can be answered with a huge and costly scientific program in place.

At the same time and from an ethical perspective, I must add that I find this proposal strained at best. Winding the clock back on a developed somatic cell and to stop it at a critical point is supposed to be void of ethical issues while letting a cell grow forward to just before the same point as with SCNT is not ethical?

This is the potentiality argument in reverse. In one version the film of life is running forward and in the other it is running in reverse. In both scenarios humans are making decisions about life and its origins. It reveals how the so-called ethical concerns are being laid over molecular events moving either forward or backward in time.

In summary, these proposals, in spite of being experimentally approachable, are, ultimately, high-risk gambles. Each presents formidable, but not impossible, technical problems. The scientific challenges must not be confounded with the complex moral issues. Most troubling, this effort dilutes the essential question: Is the United States of America going to allow embryonic stem cell research and biomedical cloning to go forward using the now widely accepted techniques used by the private sector, by the State of California, and by dozens of other countries, or is it going to remain hostage to the arbitrary views of those with certain beliefs about the nature of life and its origins?

Michael S. Gazzaniga

***

Personal Statement of Professor George (joined by Professor Glendon and Dr. Gómez-Lobo)

I support the Council's efforts to identify means of obtaining human pluripotent stem cells for biomedical research that do not involve killing or harming human embryos and do not invite the exploitation of women to obtain ova. If such means can be identified, research involving embryonic or embryonic-type stem cells could go forward, and be funded by the federal government, without ethical qualms and controversy. Assuming that supporters of embryonic stem cell research and its public funding are sincere in saying that they have no intention or desire to derive tissue or organs from post-implantation human embryos or from human fetuses, this would bring to a close-honorably and without rancor-a divisive chapter in our recent history. Frankly, I do not see how any person of goodwill could be opposed to such a resolution of the matter.

I commend everyone who has stepped forward to propose possible methods of obtaining human pluripotent stem cells while fully respecting human life at every stage of development. I thank our Council's staff and consultants who have helped to provide in this White Paper a thorough, if necessarily in some ways still preliminary, analysis of each of the four proposals we sketch and analyze. Although I do not hold out hope of obtaining pluripotent stem cells harmlessly via blastomere extraction from living human embryos (proposal II), I believe that each of the other three proposals merits further exploration (including, where indicated, experimental research involving non-human animal cells) and analysis.

The best long-term solution is likely to be somatic cell dedifferentiation (proposal IV). But while scientists work towards the goal of dedifferentiating somatic cells back to their corresponding progenitor cells, it may be possible ethically to employ one or both of the other two methods, namely deriving cells from embryos that have died (proposal I) or from nonembryonic entities produced by altered nuclear transfer (proposal III). I say, with emphasis, may be because serious moral and practical concerns have been raised about both proposals. Research and further analysis will be required to determine whether the proposed methods are technologically possible and ethically sound. That research and analysis should, in my opinion, go forward.

Of the four possible methods explored in our White Paper, the one that has attracted the most intense interest outside the Council is altered nuclear transfer. There are two major concerns: (1) the question whether the entity produced would be truly non-embryonic, and not a disabled embryo or an embryo genetically programmed for a premature death; and (2) the question whether ova could be supplied without subjecting women to the painful and possibly dangerous process of superovulation. Neither of these questions is, strictly speaking, ethical, though both have what I consider to be decisive ethical implications. Like Dr. Hurlbut, who has taken the lead in formulating this proposal, I will not support altered nuclear transfer as a method of obtaining human pluripotent stem cells unless it can be shown that (1) the procedure truly and reliably produces nonembryonic entities, rather than damaged embryos, and (2) it is possible to carry out altered nuclear transfer on the scale required without subjecting women to harmful and exploitative practices.

I recognize that some people have objections to altered nuclear transfer even if these conditions are met. Dr. Krauthammer, for example, objects even if the sources of stem cells created can be shown truly to be nonembryonic. Because Dr. Krauthammer also objects (as I do) to the creation for destruction of true embryos (by cloning or any other method), I take his concerns very seriously and welcome his criticisms of my own more permissive view. I would not finally endorse altered nuclear transfer using human cells prior to engaging the argument with him more fully and considering with the utmost care the considerations he adduces against it.

It is more difficult to credit the ethical objections to altered nuclear transfer of those who support the creation of true embryos to be destroyed in biomedical research. How can it be right deliberately to create and destroy true human embryos-beings that no one can deny are human individuals in the embryonic stage of development-yet somehow wrong to produce disorganized growths that are the moral equivalent of gamete tumors rather than embryos?

One final point: the effort in which I am happy to join to find morally legitimate means of obtaining embryonic or embryonic-type stem cells should not be interpreted as indicating any acceptance of the hyping of the therapeutic promise of embryonic stem cell research that has marred the debate over the past four years. This promotion of exaggerated expectations dishonors science and shames those responsible for it by cruelly elevating the hopes of suffering people and members of their families. It should be condemned.

Robert P. George

(joined by Mary Ann Glendon and Alfonso Gómez-Lobo)

Personal Statement of Dr. Hurlbut

Since I find myself in the unusual position of being both a member of the Council and, at the same time, the principal advocate of one of the four proposals here under consideration, I am mindful that a delicate balancing of roles is required in the way I frame the following remarks. I shall take care that my comments not cross the line separating impartial analysis of the four proposals from partisan advocacy of one of them.

While I believe that, by and large, the White Paper, like a good preliminary hearing at law, does an admirable job of presenting the four proposals and beginning their ethical, scientific, and practical analysis, it seems to me deficient in two main respects. First, I think there is much more to be said about the importance, for the future, of finding a scientific and ethical solution to the problem of deriving human stem cell lines. Second, I think that some of the ethical concerns raised about the ANT proposal could have been answered more effectively. In the brief remarks that follow, I will try to supply these two deficiencies.

In our report Human Cloning and Human Dignity: An Ethical Inquiry (July 2002), I joined colleagues who called for a moratorium on cloning-for-biomedical-research. I believed that our nation needed time to consider more thoroughly the moral status of ex vivo human embryos and to seek scientific methods for procuring embryonic stem cells that could sustain social consensus for a unified federal policy. This White Paper both deepens the dialogue and encourages progress toward these goals, but it does not make it sufficiently clear why it is urgent that we succeed.

The past three years have been characterized by controversy about the scientific prospects for embryonic (versus adult) stem cells and a widening political divide over the ethics of ESC research. Advances have been made in the study of ES cells, yet predictions of imminent cures have been moderated by a recognition of the technical difficulties in emulating in vitro the intercellular signals and microenvironments that promote cell differentiation within natural embryogenesis. Nonetheless, scientists generally believe that ESC research is both essential to the broader study of both natural development and pathogenesis and promising for medical interventions against a range of serious diseases. They also believe that, without NIH support for newly created ES cell lines, progress in this important realm of research will be severely constrained.

Yet even as these scientific prospects have become clearer, advances in our understanding of developmental biology have strengthened the case of those with ethical objections to embryo destruction. New scientific evidence supports the idea that there is an integrated unity and unbroken continuity of development from fertilization onward-and undercuts claims that the early embryo is an "inchoate clump of cells," available for instrumental use with little or no moral concern.

These findings have solidified the convictions of many people that any instrumental use of human embryos must be acknowledged as a choice for destruction of human life (albeit at a very early stage of development), justified not by scientific evidence or moral reason but by a purely utilitarian calculus based on the promise of cures and even commercial considerations. This approach, grounded not on principle but on a balance of benefits, would seem vulnerable to being easily persuaded toward additional exceptions and extensions as further promising projects become evident.

Beyond their destruction for the procurement of ES cells, some fear the industrial scale production of living human embryos for a wide range of research in natural development, toxicology, and drug testing. These concerns have already been aggravated by proposals to use ES cells in the creation of human-animal chimeras, including projects involving their gestation to various stages of development in the wombs of animals. Furthermore, some see ominous implication in the evidence that later stage human embryos (beyond 14 days) can provide the critical conditioning environment for the transformation of adult stem cells into useful cell types, tissues, and possibly organs.

Our current conflict over the moral status of the human embryo reflects deep differences in our basic convictions and is unlikely to be resolved through deliberation or debate. Likewise, a purely political solution will leave our country bitterly divided, eroding the social support and sense of noble purpose that is essential for the public funding of biomedical science. Furthermore, the emerging patchwork of state policies threatens to create a situation in which many patients will enter the hospital with qualms about the moral foundations on which their treatments have been developed. The traditional sanctuary of compassionate care at the most vulnerable and sensitive moments of human life is becoming an arena of controversy and conflict.

As we enter the era of developmental biology, we will face many more moral dilemmas; the current conflict over ES cells is just the first of a series of difficult controversies over the experimental use of emerging life that will require us to define with clarity and precision exactly which boundaries we seek to defend. Chimeras, parthenotes, and projects involving the reaggregation of ES cell products will continue to challenge our definitions of human life. How we act now in the stem cell dilemma will set a precedent for all future efforts to exploit nascent human life for scientific ends. There is thus much more at stake than the proposals herein discussed.

The proposals presented in this White Paper open a realm of intellectual inquiry and creative scientific investigation in the search for a solution to our current impasse over the procurement of embryonic stem cells. Such a solution must be grounded in deep ethical reflection and in careful preliminary studies with animal cells. The incommensurate good of human life, and the corresponding danger of its instrumental use (thereby violating the principle we are trying to protect), mean that the highest levels of caution must prevail as we proceed forward with this project. We must initiate the cooperative dialogue that is essential to frame the moral principles that can at once defend human dignity and promote the fullest prospects for scientific progress and its medical applications.

2.    Answers to ethical concerns raised about ANT

Throughout this report we draw a distinction between pluripotency, the capacity to give rise to many if not all the different cell types of the human body, and totipotency, the capacity to give rise to the whole organism as an integrated living being. Employing these concepts in the search for a technological solution to our ethical impasse, we must consider any entity that has the intrinsic potential to develop as a human organism (totipotency) as bearing the inviolability of a human life. This status applies regardless of its means of production or present location.

Proposals 1 (Landry-Zucker) and 3 (Altered Nuclear Transfer) may hold the best near-term promise for practical application, yet they also raise the most difficult conceptual considerations. Landry-Zucker would extract ES cells from embryos that are no longer totipotent, and Altered Nuclear Transfer (ANT) would create and extract ES cells from "biological artifacts" that never rise to the level of totipotency. Both proposals shift the ethical debate from the question of when a normal embryo is a human being with moral worth, to the more fundamental question of what component parts and organized structure constitute the minimal criteria for considering an entity a living human organism.

Each of these proposals draws on the idea that a living organism is a self-subsisting being, a coordinated and coherent whole with the capacity for self-directed development, maintenance, and repair. The very word organism implies organization, an overarching principle of unity, a cooperative interaction of interdependent parts subordinated to the good of the whole. For an embryonic organism, this implies an inherent potency, a drive in the direction of the mature form. By its very nature, an embryo is a developing being, its wholeness defined by both its manifest expression and its latent potential; it is the phase of human life in which the organismal whole produces its organic parts.

For Landry-Zucker, the conceptual and moral challenge is to define the meaning of "embryo death," the cessation of integrated form and the totipotent capability that characterizes a living human embryo. A secondary, scientific challenge is to identify a physical marker of this state. For Altered Nuclear Transfer, the conceptual and moral challenge is the more difficult task of defining the boundary between mere cellular growth lacking integrated form and a living organism. The scientific challenge of ANT is to find the right genetic or epigenetic alteration to ensure that pluripotent cells can be produced while not creating an embryonic human being. It is here that the White Paper, in my view, does not make sufficiently clear how the proposal in fact meets that challenge.

That an ANT product might during its earliest stages visually resemble an embryo does not make it an embryo, for an entity's fundamental nature must ultimately be based on its internal biochemical structure and organization. Likewise, cell division and growth are not sufficient evidence that the entity is a human embryo. Even an egg without a nucleus, when artificially activated, has the developmental power to divide to the eight-cell stage, yet clearly is not an embryo, or even an organism. Moreover, the possibility that the alteration could be reversed does not affect the fact that the targeted alteration has preempted the ANT entity from having the nature (the ontological status) of an embryo.

The product of ANT would, by intention, lack the active potential and inviolable moral nature of a living human being. Without this moral standing, there is no obligation of repair because there is no living being to be repaired. Nonetheless, even such a limited biological entity should be accorded a certain cautionary respect as with all human tissues, though not the full protection of human life.

Some fear that the precedent of intentional genetic intervention (essential to ANT), and its justifying argument based on the intrinsic insufficiency of the entity produced, could become the basis for further projects in the bioengineering of ever more human-like "intermediate biological forms." This is a serious consideration, but one that would be better addressed to those who maintain an "intermediate moral status" (worthy of dignity but not inviolability) for the human embryo and already accept the destruction of fully normal human beings at an early stage of their development.

The very foundation of the moral argument for ANT should work to mitigate the concerns about the "slippery slope" potential for ES cell research. Since ANT seeks to defend human dignity from conception, it is less likely to lead to such indiscriminate and instrumental use of human life than the practices it seeks to preempt. By establishing a principled concern for the protection of human life from fertilization to natural death, ANT sets a firm foundation for the later distinctions necessary for further moral discrimination. Other proposals for the procurement of ES cells (SCNT and "leftover" IVF embryos) give little or no guidance to override the persuasive power of further promise from extending exceptions to moral principles. By establishing the primacy of ethical principle as the foundation of all scientific progress, ANT could help set the foundation and frame for the additional ethical dilemmas that will inevitably arise with advances in developmental biology. The difficult definitions and distinctions established in the moral deliberations associated with the ANT proposal could help chart the course and protect the path of future projects in this emerging arena of biology. If slippery slope arguments express prudential concerns, it seems reasonable to weigh ANT against the much more slippery scenario that will likely follow in its absence.

Finally, there is the less easily argued but wider wisdom of our intuitive aesthetic response, and the concern that somehow we may violate or distort the principles of natural order that sustain the coherence and sense of significance of human life. I consider this the most compelling objection to both ANT and the whole of the modern project of biological intervention in the natural world. Clearly, no project that enters into such proximity with the most central and sacred realms of human life should be undertaken without a sense of cautionary concern and serious purpose. Employing these powers of our most basic biology demands a sensitive awareness of the radiance of respect that must attend any technological use of body parts or processes apart from their proper place in the larger purposes of life. Nonetheless, where great good is possible, human tissues and organs have been used in the service of healing, and in this coming era of control over the primary forces of developmental biology, we will learn to use partial trajectories of organic growth even apart from their context within the living whole of the human body. The moral concerns and sensitivities that animate the proposal for ANT can, in fact, enable us to do so without losing our humanity.

William B. Hurlbut

Personal Statement of Dr. Rowley

Landry and Zucker propose to thaw out embryos to follow the natural history of "dead" embryos. Because they do not know in advance which embryos will not divide and which will, some portion of embryos (about half) will continue to divide and will be healthy embryos. What happens to these healthy embryos? The proposal says healthy embryos in excess of those to be implanted will be allowed to die while scientists struggle to recoup a few living cells from the dead embryos! This seems to me to be the height of folly. As noted on page 21 in a footnote, I raised this concern during the public discussion.

I think this is risky research, although I recognize it is currently done as part of prenatal genetic diagnosis. In the latter case, it is done to prevent implantation of an embryo with a serious disease present in the parents; in the former, in the present proposal, it is done to circumvent a problem that causes ethical concerns to some people. There are at least two critical questions: can you get a cell line from one cell or two, and does it harm the embryo that will subsequently be implanted? Just because experiments in mice seem to indicate that it is feasible in mice (but with increased inter-uterine mortality), does not mean it will work for human embryos. In support of this proposal, it is absurd to say that this cell line, if it grows, will be a source of cells for the child later in life. A much more effective procedure would be to harvest stem cells from the cord blood and preserve them.

This proposal is scientifically unsound, and for individuals concerned about manipulating human oocytes for experiments, it should be ethically unacceptable! It has proven very inefficient to remove the nucleus from a human oocyte and to replace it with a normal, unmanipulated nucleus from a donor. In the proposed experiments, the donated nucleus will be made defective by some uncertain genetic strategy. The defective nucleus will be inserted into the enucleated oocytes, the oocytes will be stimulated to grow, and then the genetic defect will be corrected so that the cells are "normal." In my view, this research asks women to donate oocytes for research that is highly unlikely to result in cell lines that would be useful for treating sick patients, which is the purpose of trying to perfect the development of human embryonic stem cell lines.

This proposal does not involve embryos, but rather differentiated cells. The purpose aims to dedifferentiate these cells. At least some of the purported successes with this strategy have had flaws when examined carefully. This proposal should be submitted to the National Institutes of Health and if it passes peer review with a sufficiently high score to be funded, then the research will go forward.

My concerns with many of these proposals is that they will use financial resources that would be better devoted to proposals that are likely to be more productive. I find the notion that it is ethically sound to let healthy embryos die rather than use them to try to develop cell lines that could benefit sick and dying patients totally baffling. We talk about protecting human dignity. We should strive to help patients with serious illnesses that could potentially be treated with embryonic stem cells to live as fulfilling and dignified lives as is humanly possible. The research proposed in this White Paper largely fails to achieve this good, and thus I cannot support proposals I, II and III.

Janet D. Rowley

***

Personal Statement of Professor Sandel

I share the goal of seeking ethically uncontroversial ways of pursuing embryonic stem cell research. In my view, the first proposal (deriving cells from dead embryos) and the fourth (somatic cell dedifferentiation) are ethically acceptable and worthy of further exploration. I find the third proposal (deriving cells from specially engineered biological artifacts) to be morally objectionable.

As one who supports embryonic stem cell research, I do not regard the early embryo as inviolable. But neither do I regard it as disposable, open to any use we may desire or devise. For this reason, embryo research carries a special moral burden; it is justified only for the sake of saving human lives or curing devastating diseases. The proposal to genetically engineer a nonviable, embryo-like being would remove the moral burden by creating something that, lacking the capacity to develop into a human person, would be wholly disposable, presumably for any purpose, weighty or trivial. The very project of creating such a being is morally troubling, for reasons that are well-stated in the ethical analysis (pp. 38-45 above). I therefore do not believe that this proposal should be encouraged or endorsed.

Michael J. Sandel

Next Chapter